Project Summary/Abstract Postural tachycardia syndrome (POTS), is the chronic form of orthostatic intolerance associated with excessive upright tachycardia, and occurs predominantly in young females (>85%). Among its most troubling symptoms are lightheadedness, fatigue, and decreased memory often called ?brain fog? by patients. Task-related neurovascular coupling (NVC) links neural activity to an increase in CBF known as ?functional hyperemia?. Although memory task performance and NVC deteriorated with angle of tilt in POTS but not healthy controls, cerebral blood flow (CBF) remained similar to control. Instead, we observed extensive narrow band low frequency (0.07-0.13 Hz) oscillations in BP (OBP) that entrained and amplified oscillations in CBF (OCBF). OBP and OCBF increased with tilt angle and caused impaired working memory and reduced functional hyperemia. The cardiovagal baroreflex couples BP to HR to buffer BP changes. We hypothesize that the cardiovagal baroreflex becomes progressively impaired with orthostasis in POTS, but not in healthy volunteers, and accounts for OBP, OCBF, and loss of NVC; further, improving the baroreflex reduces OBP, OCBF and Brain Fog in POTS. We will recruit female POTS subjects aged 15-30 years (N=60) off medication and free of other systemic disease, and healthy subjects (N=20). Our approach is three-fold: 1) we will use the reference standard modified Oxford technique to measure the cardiovagal baroreflex, and assess working memory and functional hyperemia while POTS and healthy subjects undergo a graded upright tilt from supine to 60o in15o increments. We anticipate step-wise increased OBP and OCBF at low frequency in POTS, with step-wise decreased functional hyperemia and performance on an N-Back memory task 2) We will externally force OBP and OCBF using oscillatory lower body negative pressure to demonstrate the causal connection between OCBF and decreased functional hyperemia and performance on an N-Back memory task 3) We will compare the acute effects of digoxin and pyridostigmine, against placebo using the experimental methods of approach 1) above. Literature suggest that these drugs increase cardiovagal baroreflex and improve parasympathetic tone in sickness and in health; they may reduce tachycardia and symptoms in POTS. This work will not only furnish a link between impaired cardiovagal baroreflex and cognitive loss in POTS, but may find applicability in diverse circulatory illnesses in which baroreflex deficits appear.